When a patient is faced with an orthopedic injury, such as an injury to the Anterior Cruciate Ligament (ACL), the ideal solution to this ailment would be to repair this structure or augment the natural healing process in a way which would re-establish the morphology as it was prior to injury. Unfortunately, ACL repair and regeneration to date has been shown to be unsuccessful primarily due to the lack of healing/regrowth of the native tissues naturally; therefore, total replacement has been the standard of care. Replacement of the ACL via donated human cadaver (i.e. allograft) tendons has proven to be an efficacious option allowing patients to return to their pre-injury quality of life. However, allograft options are burdened with the challenge of depending on a raw material that has large variability and limited availability. Surgeons have tried to mitigate graft variability by limiting donor criteria (e.g. only accepting grafts from donors <45 years of age); however, such limitations have also exacerbated the availability challenge.
Thus, a goal is to find a sufficient pool of donor tissue, with similar genetic, physical and physiological attributes, that could mitigate or eliminate the above problems. This can be done by utilizing xenograft tissue. With a xenograft tissue source donor genetic makeup can be selected and controlled through breeding and herd management, production can be monitored and controlled to ensure the best health and muscle tone, and donor age can be planned and selected. Such donors would thus have exceptional biomechanical structures available for creating high quality grafts which would be recovered from them at their peak age.
Implants comprising soft tissues may be implanted into a recipient to replace and/or repair existing soft tissues. For example, hereditary defects, disease, and/or trauma may damage soft tissues such that replacement and/or repair is desirable. These implants may be allografts, autografts, or xenografts, and the recipients may be human, mammal, or animal recipients. Implants are frequently used where the recipient is a human patient. Implants comprising soft tissues have been used, including in human patients, to replace heart valves, ligaments, tendons and skin, among other tissues.
It is desirable to treat implants, particularly autografts, allografts, and xenografts, to neutralize, remove or substantially reduce one or more undesirable components and/or to instill one or more desirable components. For example, implants may be passivated, or treated to remove or inactivate bacteria, viruses, fungi and other pathogens and antigenic constituents.
Implants comprising soft tissues may be treated with cleaning agents and/or gamma radiation. However, existing techniques suffer from one or more disadvantages. Undesirable results from radiation can include formation of radicals, hydrogen, and low-molecular-weight hydrocarbons; increased unsaturation; discoloration; and oxidation. The use of some chemical sterilizing agents (for example, glutaraldehyde) increases the risk that a toxic response will be evoked. Furthermore, some chemical sterilizing agents (for example, peroxides) may damage the implant, particularly soft tissues, which tend to be somewhat more fragile than bone and hard tissues. A particular concern with the passivation of implants comprising soft tissues is that treated soft tissue may suffer from increased laxity, reduced stiffness, reduced strength, or reduced biocompatibility, which can lead to variable performance of the implant. It is desirable to have treatment processes, including a process for passivation, that does not cause excessive laxity or reduction in stiffness or strength or biocompatibility of the soft tissue.
Gamma irradiation, in order to ensure destruction of pathogens, such as the human immunodeficiency virus (HIV), has been used at doses that result in tissue destruction (e.g. 3.5 Mrad; see, for example, Rasmussen, et al., J. Arthroscopic and Related Surgery, 10(2):188-197, (1994); Goertzen, et al., British Soc. of Bone and Joint Surg., 77:204-211 (805); Loty, et al., International Orthopaedics, 14:237-242, (1990)). Use of ethylene oxide has been found to result in implants that produce inflammatory responses (Kudryk, et al., J. Biomedical Materials, 26:1477-1488, (1992); Thoren, et al., Clin. Orthopaedics, 318:259-263, (1995); Simonian, et al., Clin. Orthopaedics, 302:290-296, (1994); Jackson, et al., Am. J. Sports Medicine, 18:1-9, (1990)). Standard chemical solution treatments, while effective in sterilizing surfaces with which the solutions are brought into contact, tend to be insufficiently penetrating to reach the interstices of tissues, where potentially pathogenic organisms may reside. With regard to sterilization of soft tissue, the potential for damage to the soft tissue by irradiation, ethylene oxide, or chemical solution treatment is of particular concern, because soft tissue are more susceptible to damage than bone tissue. Even milder sterilants such as peroxides may cause damage due to swelling of the tissues and the presence of residual reaction byproducts.
A desirable treatment process includes one or more of the following features: effective removal or inactivation of a wide range of bacterial, viral and fungal pathogens; absence of graft toxicity; retention or improvement of desirable tissue characteristics, such as biomechanical strength or growth-inducing properties; effectiveness across a wide range of operating modifications and/or for a wide variety of tissue types; ability to conclude the process in a final implant tissue container, to ensure sterile packaging and delivery for implantation; ability to apply automated control and monitoring systems and develop an automated and validated process.
A challenge associated with developing a xenograft implant is sufficient removal of foreign xeno-antigens. The presence of such epitopes, specifically Galα1-3Gal_1-4GlcNAc-R (often referred to as alpha-gal) is important to neutralize, remove or substantially reduce due to the human body having antibodies which specifically target this glycoconjugate. Grafts derived from xenographic sources that contain this xeno-antigen are acutely rejected by the human body once implanted.